Identification of Deregulated Signaling Pathways in Jurkat Cells in Response to a Novel Acylspermidine Analogue-N4-Erucoyl Spermidine

Natural polyamines such as putrescine, spermidine, and spermine are crucial in the cell proliferation and maintenance in all the eukaryotes. However, the requirement of polyamines in tumor cells is stepped up to maintain tumorigenicity. Many synthetic polyamine analogues have been designed recently to target the polyamine metabolism in tumors to induce apoptosis. N4-Erucoyl spermidine (designed as N4-Eru), a novel acylspermidine derivative, has been shown to exert selective inhibitory effects on both hematological and solid tumors, but its mechanisms of action are unknown. In this study, RNA sequencing was performed to investigate the anticancer mechanisms of N4-Eru-treated T-cell acute lymphoblastic leukemia (ALL) cell line (Jurkat cells), and gene expression was examined through different tools. We could show that many key oncogenes including NDRG1, CACNA1G, TGFBR2, NOTCH1,2,3, UHRF1, DNMT1,3, HDAC1,3, KDM3A, KDM4B, KDM4C, FOS, and SATB1 were downregulated, whereas several tumor suppressor genes such as CDKN2AIPNL, KISS1, DDIT3, TP53I13, PPARG, FOXP1 were upregulated. Data obtained through RNA-Seq further showed that N4-Eru inhibited the NOTCH/Wnt/JAK-STAT axis. This study also indicated that N4-Eru-induced apoptosis could involve several key signaling pathways in cancer. Altogether, our results suggest that N4-Eru is a promising drug to treat ALL.

[1]  Paula Esther Moraga-Serrano.  Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016:A Systematic Analysis for the Global Burden of Disease Study , 2018 .

[2]  D. Pinto,et al.  Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application , 2018, International journal of molecular sciences.

[3]  M. Alhosin,et al.  Synthesis, screening and pro-apoptotic activity of novel acyl spermidine derivatives on human cancer cell lines. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[4]  Jun J. Yang,et al.  Pharmacogenomics in acute lymphoblastic leukemia. , 2017, Best practice & research. Clinical haematology.

[5]  Y. Mély,et al.  The epigenetic integrator UHRF1: on the road to become a universal biomarker for cancer , 2017, Oncotarget.

[6]  C. Bronner,et al.  Signalling pathways in UHRF1-dependent regulation of tumor suppressor genes in cancer , 2016, Journal of experimental & clinical cancer research : CR.

[7]  Ashutosh Kumar Singh,et al.  Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015 , 2016, The Lancet.

[8]  Ashutosh Kumar Singh,et al.  Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015 , 2016, Lancet.

[9]  M. Liedtke,et al.  Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. , 2016, The New England journal of medicine.

[10]  Mario Cazzola,et al.  The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. , 2016, Blood.

[11]  Andrew D. Rouillard,et al.  Enrichr: a comprehensive gene set enrichment analysis web server 2016 update , 2016, Nucleic Acids Res..

[12]  Jianlin Cheng,et al.  Inhibition of Hedgehog-Signaling Driven Genes in Prostate Cancer Cells by Sutherlandia frutescens Extract , 2015, PloS one.

[13]  Jaak Vilo,et al.  ClustVis: a web tool for visualizing clustering of multivariate data using Principal Component Analysis and heatmap , 2015, Nucleic Acids Res..

[14]  J. Pincemail,et al.  Bilberry extract (Antho 50) selectively induces redox-sensitive caspase 3-related apoptosis in chronic lymphocytic leukemia cells by targeting the Bcl-2/Bad pathway , 2015, Scientific Reports.

[15]  G. Banfalvi,et al.  Methotrexate induced apoptotic and necrotic chromatin changes in rat myeloid leukemia cells , 2015, Inflammation Research.

[16]  Yu Zhang,et al.  Upregulated UHRF1 Promotes Bladder Cancer Cell Invasion by Epigenetic Silencing of KiSS1 , 2014, PloS one.

[17]  J. Rolain,et al.  Mini-Review: Polyamines Metabolism, Toxicity and Potent Therapeutical Use , 2014 .

[18]  V. Tumiatti,et al.  Synthetic polyamines activating autophagy: effects on cancer cell death. , 2013, European journal of medicinal chemistry.

[19]  Edward Y. Chen,et al.  Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool , 2013, BMC Bioinformatics.

[20]  P. Woster,et al.  Polyamines and cancer: implications for chemotherapy and chemoprevention , 2013, Expert Reviews in Molecular Medicine.

[21]  H. E. Johansson,et al.  Depletion of cellular polyamines, spermidine and spermine, causes a total arrest in translation and growth in mammalian cells , 2013, Proceedings of the National Academy of Sciences.

[22]  M. Ceccarelli,et al.  UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression , 2012, Oncogene.

[23]  P. Kufer,et al.  Blinatumomab: a historical perspective. , 2012, Pharmacology & therapeutics.

[24]  Kiran C. Bobba,et al.  The genetic basis of early T-cell precursor acute lymphoblastic leukaemia , 2012, Nature.

[25]  F. Huguet.  [Adult acute lymphoblastic leukemia]. , 2011, La Revue du praticien.

[26]  Gary D. Bader,et al.  The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function , 2010, Nucleic Acids Res..

[27]  T. Sharif,et al.  Induction of apoptosis by thymoquinone in lymphoblastic leukemia Jurkat cells is mediated by a p73-dependent pathway which targets the epigenetic integrator UHRF1. , 2010, Biochemical pharmacology.

[28]  Anna Minarini,et al.  Cytotoxicity of methoctramine and methoctramine-related polyamines. , 2009, Chemico-biological interactions.

[29]  P. Woster,et al.  Design of polyamine-based therapeutic agents: new targets and new directions. , 2009, Essays in biochemistry.

[30]  Cheng Cheng,et al.  Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. , 2009, The Lancet. Oncology.

[31]  P. Woster,et al.  Polyaminohydroxamic acids and polyaminobenzamides as isoform selective histone deacetylase inhibitors. , 2008, Journal of medicinal chemistry.

[32]  M. Relling,et al.  Childhood Acute Lymphoblastic Leukaemia , 2007 .

[33]  S. Baylin,et al.  Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes , 2007, Proceedings of the National Academy of Sciences.

[34]  D. Gold,et al.  Novel role of HDAC inhibitors in AML1/ETO AML cells: activation of apoptosis and phagocytosis through induction of annexin A1 , 2007, Cell Death and Differentiation.

[35]  M. Esteller.  Cancer epigenomics: DNA methylomes and histone-modification maps , 2007, Nature Reviews Genetics.

[36]  P. Woster,et al.  Alkyl-substituted polyaminohydroxamic acids: a novel class of targeted histone deacetylase inhibitors. , 2005, Journal of medicinal chemistry.

[37]  E. Sausville,et al.  Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  P. Pandolfi,et al.  Regulation of the p73 protein stability and degradation. , 2005, Biochemical and biophysical research communications.

[39]  J. Cleveland,et al.  Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation. , 2005, Cancer cell.

[40]  T. Yao,et al.  FBW2 Targets GCMa to the Ubiquitin-Proteasome Degradation System* , 2005, Journal of Biological Chemistry.

[41]  N. Davidson,et al.  Molecular mechanisms of polyamine analogs in cancer cells. , 2005, Anti-cancer drugs.

[42]  Leo Koenderman,et al.  Signal transducer and activator of transcription 5 (STAT5). , 2004, The international journal of biochemistry & cell biology.

[43]  E. Gerner,et al.  Polyamines and cancer: old molecules, new understanding , 2004, Nature Reviews Cancer.

[44]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[45]  T. Thomas,et al.  Polyamine metabolism and cancer , 2003, Journal of cellular and molecular medicine.

[46]  W. Kamps,et al.  Vincristine induced apoptosis in acute lymphoblastic leukaemia cells: a mitochondrial controlled pathway regulated by reactive oxygen species? , 2002, International journal of oncology.

[47]  Sang-Gu Hwang,et al.  Anticancer drugs-induced apoptotic cell death in leukemia cells is associated with proteolysis of β-catenin , 2002 .

[48]  Ricky W. Johnstone,et al.  Histone-deacetylase inhibitors: novel drugs for the treatment of cancer , 2002, Nature Reviews Drug Discovery.

[49]  M. Burns,et al.  Novel lysine-spermine conjugate inhibits polyamine transport and inhibits cell growth when given with DFMO. , 2000, Experimental cell research.

[50]  R. Nusse,et al.  Wnt-induced dephosphorylation of axin releases beta-catenin from the axin complex. , 1999, Genes & development.

[51]  K. Fukuda.  Apoptosis-associated cleavage of beta-catenin in human colon cancer and rat hepatoma cells. , 1999, The international journal of biochemistry & cell biology.

[52]  R. Ross,et al.  Cleavage of beta-catenin and plakoglobin and shedding of VE-cadherin during endothelial apoptosis: evidence for a role for caspases and metalloproteinases. , 1998, Molecular biology of the cell.

[53]  Pui,et al.  Childhood Acute Lymphoblastic Leukemia. , 1997, The oncologist.

[54]  M. Ozawa,et al.  Expression of cadherin-catenin complexes in human leukemia cell lines. , 1996, Journal of biochemistry.

[55]  H. Dohy,et al.  Cancer incidence in atomic bomb survivors. Part III. Leukemia, lymphoma and multiple myeloma, 1950-1987. , 1994, Radiation research.

[56]  B. Feuerstein,et al.  Implications and concepts of polyamine‐nucleic acid interactions , 1991, Journal of cellular biochemistry.

[57]  Edwin A. Paz,et al.  Polyamines in cancer. , 2011, Advances in clinical chemistry.

[58]  Claire Schwab,et al.  Acute lymphoblastic leukaemia. , 2011, Methods in molecular biology.

[59]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[60]  D. Levi.  Editorial board , 2007, Vision Research.

[61]  M. Krajinovic,et al.  [Pharmacogenomics of acute lymphoblastic leukemia]. , 2007, Medecine sciences : M/S.